Human milk is the preferred form of infant nutrition for the first six months of life as recommended by the American Academy of Pediatrics and the World Health Organization. It contains various antibodies and immune cells, along with compounds that prevent pathogenic bacteria or toxins from binding to receptors, such as lysozyme, lactoferrin, and other oligosaccharides (Yilmaz, et al., Interleukin-10 and -12 in human milk at 3 stages of lactation: a longitudinal study. Adv Ther. 2007 May-June; 24(3):603-10). In addition to immune factors, there are hormones and other growth factors, such as epidermal growth factor (EGF), cytokines, such as transforming growth factor (TGF), and chemokines, including various interleukin proteins (IL-6, IL-8, IL-10, IL-13) and tumor necrosis factor proteins (TNFα and TNF-R) (Castellote, et al., Premature delivery influences the immunological composition of colostrum and transitional and mature human milk. J Nutr. 2011 June; 141(6):1181-7). For the first few days after birth, colostrum is expressed from the mammary glands. During this period the tight junctions of the mammary glands are open allowing for transport of components of the maternal blood, resulting in a composition having markedly different biochemical characteristics from mature milk (Espinosa-Martos, et al., Bacteriological, biochemical, and immunological modification in human colostrum after Holder pasteurization. J Pediatr Gastroenterol Nutr. 2013 May; 56(5):560-8). During lactation, the composition changes as the milk transitions from colostrum to mature milk (Castellote, et al., Premature delivery influences the immunological composition of colostrum and transitional and mature human milk. J Nutr. 2011 June; 141(6):1181-7).
There are an estimated 15 million preterm infants born each year, which account for approximately 12% of the births (World Health Organization, Fact Sheet No. 363, last updated November 2014). The colostrum of preterm mothers expresses high levels of immunologic proteins, growth factors, and cytokines which decreases throughout lactation (Castellote, et al., Premature delivery influences the immunological composition of colostrum and transitional and mature human milk. J Nutr. 2011 June; 141(6):1181-7; FIGS. 1 & 2). Due to the unique composition of preterm milk, mothers of preterm infants are encouraged to express colostrum, and to establish lactation and pump as much as possible in the ensuing weeks. The American Academy of Pediatrics Recommendations of Breastfeeding Management for Preterm Infants state that all preterm infants should receive human milk and if mother's own milk (MOM) is unavailable, pasteurized donor human milk, appropriately fortified, should be used (The American Academy of Pediatrics. Breastfeeding and the use of human milk. Pediatrics. 2012; 129(3):e827-e841).
However, not all mothers choose to breast feed, or are able to breast feed, and the most vulnerable infants who require human milk are preterm infants. Moreover, maintaining lactation while separated from a very sick and small newborn must be through pumping in most cases as these infants are too small to suckle at breast. For many mothers this becomes difficult and milk volume is not maintained or there are difficulties storing and transporting the milk safely.
The alternative that is supported by the AAP is provision of human milk purchased from milk banks and provided to preterm infants in lieu of formula. Recently, there has been an escalation in the use of banked donor milk in neonatal intensive care units (NICUs), rising from 25.1% nationally in 2007 to 45.2% in 2011 (p<0.001) (Perrine & Scanlon, Prevalence of use of human milk in US advanced care neonatal units. Pediatrics. 2013; 131(6):1066-1071). This steady increase reached an all-time high of 2.15 million ounces of human banked donor milk dispensed by the Human Milk Banking Association of North America in 2011 (Updegrove, Nonprofit human milk banking in the United States [published online Jul. 29, 2013]. J Midwifery Womens Health. doi:10.1111/j.1542-2011.2012.00267.x).
Women who donate milk to milk banks (non-profit and profit) are screened carefully before being determined to be eligible. Milk produced by donor milk banks is pasteurized by the Holder method (62.5° C. for 30 minutes) to remove harmful bacteria and viruses. It is then pooled, packaged, and sold to hospitals for use in their NICUs. The banked donor milk available for purchase from milk banks is pooled from several donors and is more likely to be from mothers who delivered term versus preterm infants (Edwards & Spatz, Making the case for using donor human milk in vulnerable infants. Adv Neonatal Care. 2012 October; 12(5):273-8; quiz 279-80). This is an important distinction as preterm MOM (milk produced by mothers delivering infants at less than 37 weeks gestation) is qualitatively different from term MOM (milk produced by mothers delivering at or after 37 weeks). The literature describes benefits of banked donor milk versus formula, but there are far fewer studies comparing banked donor milk to MOM (Espinosa-Martos, et al., Bacteriological, biochemical, and immunological modifications in human colostrum after Holder pasteurisation. J Pediatr Gastroenterol Nutr. 2013 May; 56(5):560-8; Ewaschuk, et al., Effect of pasteurization on immune components of milk: implications for feeding preterm infants. Appl Physiol Nutr Metab. 2011 April; 36(2):175-82). Since 2011, only 3 additional studies have addressed differences in CCGF between banked donor milk and MOM (Espinosa-Martos, et al., Bacteriological, biochemical, and immunological modifications in human colostrum after Holder pasteurisation. J Pediatr Gastroenterol Nutr. 2013 May; 56(5):560-8; Reeves, et al. TGF-β2, a protective intestinal cytokine, is abundant in maternal human milk and human-derived fortifiers but not in donor human milk. Breastfeed Med. 2013 December; 8(6):496-502; Ewaschuk, et al. Effect of pasteurization on selected immune components of donated human breast milk. J Perinatol. 2011 September; 31(9):593-8; Groer, et al., Cytokines, Chemokines, and Growth Factors in Banked Human Donor Milk for Preterm Infants. J Hum Lact. 2014 Mar. 24; 30(3):317-323).
Holder pasteurization not only destroys bacteria, viruses, and cells but also destroys or significantly reduces levels of immune proteins such as secretory Immunoglobulin A (sIgA) (Ewaschuk et al., Effect of pasteurization on immune components of milk: implications for feeding preterm infants. Appl Physiol Nutr Metab. 2011 April; 36(2):175-82). Immunoglobulin A, the major antibody in human milk, showed a 45% reduction after pasteurization (McPherson & Wagner, The effect of pasteurization on transforming growth factor alpha and transforming growth factor beta 2 concentrations in human milk. Adv Exp Med Biol. 2001; 501:559-66; Braga & Palhares, Effect of evaporation and pasteurization in the biochemical and immunological composition of human milk. J Pediatr (Rio J). 2007 January-February; 83(1):59-63). Lactoferrin, lysozyme, and bile salt-stimulated lipase in milk are also significantly reduced by Holder pasteurization (Christen, et al., Ultrasonication and the quality of human milk: variation of power and time of exposure. J Dairy Res. 2012 August; 79(3):361-6). Heat denaturation of proteins could reduce the concentrations of other immune molecules such as cytokines, chemokines, and growth factors (CCGF), but the effects on only a few of these have been measured.
For example, one study found Holder pasteurization did not markedly affect lactose, glucose, or myoinositol concentrations in milk, but did result in the formation of lactulose and an increase in furosine concentrations (Espinosa-Martos, et al., Bacteriological, biochemical, and immunological modification in human colostrum after Holder pasteurization. J Pediatr Gastroenterol Nutr. 2013 May; 56(5):560-8).
There has been a general assumption that Holder pasteurization not only destroys bacteria, viruses, and cellular components, but also destroys or significant reduces immune proteins such as secretory Immunogloulin A. (Ewaschuk, et al., Effect of pasteurization on immune components of milk: implications for feeding preterm infants. Appl Physiol Nutr Metab, 2011 April; 36(2):175-82). Secretory IgA showed a 45% reduction after pasteurization (Braga & Palhares, (2007). Effect of evaporation and pasteurization in the biochemical and immunological composition of human milk. J Pediatr (Rio J), 83(1), 59-63; McPherson & Wagner, The effect of pasteurization on transforming growth factor alpha and transforming growth factor beta 2 concentrations in human milk. Adv Exp Med Biol. 2001; 501:559-66) the major antibody in human milk. All of the cells in milk are destroyed by this process and heat denaturation of proteins would be likely to reduce the concentrations of immune molecules such as cytokines, chemokines and growth factors (CCGF). Few cytokines have been specifically assayed. IL-10 and eythopoietin were both reported to be markedly reduced by Holder pasteurization, while epidermal growth factor (EGF) concentrations were not reduced, although all values were low before pasteurization as the mean month of lactation was 8 months, and all cytokines are higher in early lactation (Untalan, et al., Heat susceptibility of interleukin-10 and other cytokines in donor human milk. Breastfeed Med. 2009 September; 4(3):137-44). Some cytokines appear preserved after Holder pasteurization, such as TGF-β (McPherson & Wagner, The effect of pasteurization on transforming growth factor alpha and transforming growth factor beta 2 concentrations in human milk. Adv Exp Med Biol. 2001; 501:559-66). As noted in a recent review, a thorough evaluation of the effects of pasteurization on human milk is lacking (Ewaschuk, et al., Effect of pasteurization on immune components of milk: implications for feeding preterm infants. Appl Physiol Nutr Metab, 2011 April; 36(2):175-82).
Microbiota, cells, immunoglobulins, lysozyme, lactoferrin, and oligosaccharides in human milk were reported to be reduced after Holder pasteurization, but only 3 studies analyzing a limited number of CCGF had been done (McPherson & Wagner, The effect of pasteurization on transforming growth factor alpha and transforming growth factor beta 2 concentrations in human milk. Adv Exp Med Biol. 2001; 501:559-66; Untalan, et al., Heat susceptibility of interleukin-10 and other cytokines in donor human milk. Breastfeed Med. 2009 September; 4(3):137-44; Goelz, et al., Effects of different CMV-heat-inactivation-methods on growth factors in human breast milk. 2009 April; 65(4):458-61). Cytokines, chemokines, and growth factors in milk are believed to play important roles in gastrointestinal and immune development of the recipient infant (Oddy, The impact of breastmilk on infant and child health. Breastfeed Rev. 2002 November; 10(3):5-18). They affect immune modulation, maturation, and integrity of the gastrointestinal tract as well as control of inflammation in the developing recipient infant (Garofalo, Cytokines in human milk. J Pediatr. 2010 February; 156(2 Suppl):S36-40). The chemokines play a role in cellular chemoattraction and activation of neutrophils, monocytes, and lymphocytes (Garofalo, Cytokines in human milk. J Pediatr. 2010 February; 156(2 Suppl):S36-40). Cytokines, chemokines, and growth factors (CCGF) probably prime intestinal immune cells, contribute to angiogenesis, help develop the intestinal epithelial barrier function, and generally suppress inflammation (Newburg & Walker, Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res. 2007 January; 61(1):2-8). These effects may be even more important when infants are born preterm and therefore have limited in utero development of their physiological systems (Newburg & Walker, Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res. 2007 January; 61(1):2-8) Milk produced by donor milk banks is pasteurized by the Holder method (62.5° C. for 30 minutes) to destroy harmful bacteria and viruses (Updegrove, Nonprofit human milk banking in the United States. J Midwifery Womens Health. 2013 September; 58(5):502-8).
Preterm infants' risks for necrotizing enterocolitis (Sullivan, et al., An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010 April; 156(4):562-7), sepsis (Schanler, et al., Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999 June; 103(6 Pt 1):1150-7), and adverse neurodevelopment (Vohr, et al., Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007 October; 120(4):e953-9) are significantly reduced when infants receive human milk, but these protective effects could be affected by extensive or exclusive use of banked donor milk if there are lower levels of critical immune molecules.
In light of the dearth of information on the relationship between CCGF in banked donor milk and MOM, along with the importance of immunological proteins, and lactation proteins, in the development in early neonatal life, methods of supplementing donor breast milk and formula are needed in the art.